Fumiya Fukushima

Prostaglandin D2 Reinforces Th2 Type Inflammatory Responses of Airways to Low-dose Antigen through Bronchial Expression of Macrophage-derived Chemokine

PGD2, a lipid mediator released from mast cells, is known to participate in allergic reactions. However, the mechanism by which PGD2 contributes to such reactions remains unclear. We established a novel experimental model of asthma that permitted direct assessment of the role of PGD2 in airway inflammation. Antigen-sensitized mice were exposed to aerosolized prostaglandin D2 (PGD2) 1 d before challenge with low-dose aerosolized antigen. Not only the numbers of eosinophils, lymphocytes, and macrophages but also the levels of IL-4 and IL-5 in bronchoalveolar lavage fluid were higher in PGD2-pretreated mice than in control mice. The expression of macrophage-derived chemokine (MDC), a chemoattractant for Th2 cells, was greater in PGD2-pretreated mice than in control. Injection of anti-MDC antibody into PGD2-pretreated mice markedly inhibited inflammatory cell infiltration as well as Th2 cyto-kine production after antigen challenge. These results indicate that PGD2 accelerates Th2 type inflammation by induction of MDC. Our results suggest that this mechanism may play a key role in the development of human asthma and that MDC might be a target molecule for therapeutic intervention.

Production of TARC and MDC by Naive T Cells in Asthmatic Patients

The helper (Th)2 cell-attracting chemokines thymus and activation-regulated chemokine (TARC)4 and macrophage-derived chemokine (MDC) are ligands for the chemokine receptor CCR4. A number of cellular sources of TARC and MDC have been identified, including not only macrophages, dendritic cells, and natural killer cells, but also bronchial epithelial cells. Recent studies report that TARC and MDC may serve as pivotal chemokines for the development of Th2-dominated experimental allergen-induced asthma. This study was designed to assess TARC and MDC production by CD4+ T cells, including naive T cells and memory/effector T cells, purified from peripheral blood mononuclear cells in patients with asthma. Asthmatic subjects included in this study had mild asthmatic symptoms, positive skin test responses to house dust mite allergen, and elevated level of Dermatophagoides farinae immunoglobulin E in the sera. CD4+ T cells—CD45RA+CD4+ T cells—as naive T cells and CD45RO+CD4+ T cells—as memory/effector T cells—were purified by negative selection from peripheral blood mononuclear cells obtained from asthmatic patients (n = 6) and healthy controls (n = 6). These cells and established Th1/Th2 cell lines were then cultured in the presence of both anti-CD3 and -CD28 antibodies. After 48 hr of incubation, concentrations of TARC, MDC, interleukin (IL)-4, IL-5, and interferon-γ in the supernatants were measured by enzyme-linked immunoadsorbent assay. Reverse transcriptase–polymerase chain reaction was performed to analyze mRNA expression of TARC and MDC. Our results clearly showed that TARC and MDC were produced by activated CD45RA+CD4+ T cells rather than by activated CD45RO+CD4+ T cells, and the levels of these chemokines in the asthmatic patients were higher than those in the healthy controls. Furthermore, these chemokines production by Th2 cell lines were greater than those by Th1 cell lines, but the level were smaller than those by naive T cells. Our studies suggest that TARC and MDC are produced by naive T cells rather than by memory/effector T cells, including Th2 cells, in asthmatic patients, and these chemokines were produced at modest levels in any T-cell populations from healthy controls. Taken together, naive T cells in asthma have a peculiar function to produce TRAC and MDC, which contribute to local migration of Th2 cells into lung and lymphoid tissues, along with a function as precursor for memory/effector T cell. This novel function of naive T cells may be implicated in the development of asthma.

A Patient with Bronchial Asthma in Whom Eosinophilic Bronchitis and Bronchiolitis Developed during Treatment

A 56-year-old woman was referred to our hospital because of dyspnea, wheezing, and a productive cough. Eight years before presentation, bronchial asthma was diagnosed and the patient received inhaled corticosteroids plus antiasthmatic agents (a long-acting inhaled beta2-agonist, leukotriene modifiers, and theophylline). Chest radiography showed small diffuse nodular shadows, and a computed tomographic scan showed thickening of the bronchi and bronchioles, with diffuse centrilobular nodules in both lung fields. A blood test and microscopic examination of the bronchoalveolar fluid revealed marked eosinophilia. Transbronchial lung biopsy and transbronchial biopsy showed eosinophilic bronchitis and bronchiolitis. After treatment with oral prednisolone (40 mg daily) and inhaled corticosteroids, the symptoms, blood eosinophilia, and radiographic findings improved. Recently, several similar cases of eosinophilic bronchiolitis have been reported. Studies of further cases and elucidation of the pathophysiology of eosinophilic bronchiolitis are necessary to establish a concept for this disease and to determine whether it should be classified as a subtype of bronchial asthma or as a distinct entity.

A Case of Vertebral Artery Dissection Associated with Morning Blood Pressure Surge

We report a case of a middle-aged man who suffered a cerebral infarction resulting from dissection of a vertebral artery associated with morning blood pressure surge. A 56-year-old man was transferred to our hospital with dizziness and vomiting in the early morning on a cold day in winter. He reported that he had been standing in front of the sink after bathing when he suddenly felt dizzy and fell down. He did not lose consciousness, and by the time he reached the hospital by ambulance, his dizziness had subsided, but he complained of severe headache and vomited 3 times. On admission, he was alert, and there were no neurological or radiological abnormalities (CT, MR angiography) in the brain. However, infarction in the left cerebellar hemisphere was detected by brain MRI on the 5th day of hospitalization. String sign of the left vertebral artery was noted by angiography, confirming the diagnosis of dissection of the left vertebral artery. Ambulatory blood pressure monitoring was performed after discharge. Although the mean 24-h blood pressure was in the normal range, a marked morning blood pressure rise was observed. We speculated that the acute rise of blood pressure in the early morning might have contributed to the dissection of the vertebral artery.

Patients in whom active tuberculosis was diagnosed after admission to a Japanese university hospital from 2005 through 2007

To identify problems in early diagnosis of tuberculosis and to design countermeasures against the disease, we examined the status of active tuberculosis among patients admitted to a university hospital that did not have an isolation ward for tuberculosis. Between 2005 and 2007, we analyzed demographic characteristics, disease type, chest radiologic findings, and the process leading to diagnosis. Active tuberculosis was diagnosed after admission in 55 patients (34 males and 21 females): pulmonary tuberculosis, 26; tuberculous pleuritis, 13; tuberculous meningitis, 6; miliary tuberculosis, 4; tuberculous pericarditis, 3; lymph-node tuberculosis, 2; and tracheal and bronchial tuberculosis, 1. Although radiographic examinations provided abundant information, chest radiography showed normal findings in 7 patients (12.7%). Computed tomographic scanning was useful for detailed evaluation of abnormalities. Twenty patients (36.4%) were given diagnoses at departments other than ours (Department of Pulmonary Medicine). Numbers of days between hospital admission and diagnosis of tuberculosis (50th percentile/80th percentile) were 8.0/37.8 for miliary tuberculosis, 8.0/8.0 for tracheal and bronchial tuberculosis, 7.5/17.8 for tuberculous pleuritis, 7.0/8.8 for tuberculous pericarditis, 6.0/15.6 for pulmonary tuberculosis, 3.5/4.4 for lymph-node tuberculosis, and 1/1 for tuberculous meningitis. Early diagnosis of tuberculosis requires adherence to the following precautions. Tuberculosis should be suspected in any patient with respiratory symptoms. Sputum tests for acid-fast bacteria should be performed at least three times initially. If findings on chest X-ray films are equivocal, high-resolution computed tomography should be performed to confirm details of shadows and to detect minimal pulmonary shadows or cavitary lesions. Physicians from all specialties should be repeatedly informed about the risk of tuberculosis and should include tuberculosis in the differential diagnosis in patients suspected to have pulmonary diseases.

Involvement of antigen-driven mechanisms in interstitial pneumonia with polymyositis

SIR, CTDs frequently involve the lung. PM is a major CTD characterized by chronic inflammatory lesions of muscle and other organs, including critical pulmonary involvement. Interstitial lung diseases, mainly interstitial pneumonia (IP), have been recognized in 30 70% of PM patients and have a poor prognosis [1]. While the presence of myositis-specific autoantibodies, such as anti-Jo-1, and activated T-cell muscle infiltrates suggests an autoimmune etiology of PM [2, 3], the pathogenesis of PM-associated IP remains unclear. Here, we present two cases of PM-associated IP in which lung tissue was obtained from early-stage IP to perform T-cell analysis. Lung tissue was utilized with the approval of the institutional review board (bioethics committee of the Dokkyo University School of Medicine). Interestingly, both suggest the involvement of antigen-driven mechanisms in IP with PM. Patient A was a 51-year-old non-smoking woman referred to our clinic for arthralgia and myalgia. At 49 years, she noticed RP and polyarthralgia. Examination revealed fine inspiratory crackles in bibasilar lung fields. ESR and CRP were elevated at 135 mm/h and 1.2 mg/dl, respectively. Speckled ANA and anti-Jo-1 antibodies were positive. LDH and CK were elevated. Muscle strength was normal, but electromyogram showed myogenic pattern in upper limb girdle bilaterally. Muscle biopsy revealed lymphocyte infiltration into myofibrils, consistent with PM. Arterial blood gas (ABG) analysis was unremarkable. Pulmonary function tests (PFTs) revealed a restrictive pattern with vital capacity (VC) of 74.8% and diffusing capacity (DLCO) of 67.3%. Human leucocyte antigen (HLA) serotypes were as follows: A2, A26, B15 (62, 78), Cw1, Cw9, DR14, DR8, DR52, DQ7 and DQ6. Chest radiography (CXR) and CT revealed early-stage IP (Fig. 1A and B). The patient underwent lung biopsy via video-assisted thoracoscopic surgery (VATS) with biopsy specimens from the right lower lobe revealing an early usual IP (UIP) pattern (Fig. 1C). Diagnosed with PM-associated IP, the patient was treated with methylprednisolone pulse therapy (1 g/day for 3 days) followed by oral prednisolone (30 mg/day). Patient B was a 43-year-old non-smoking woman evaluated for arthralgia, myalgia and a 6-month history of RP. Fine inspiratory crackles were heard in lower lung fields. Despite no muscle weakness, thorough examination revealed myositis, with laboratory data showing elevated LDH and CK. Muscle biopsy revealed intramuscular mononuclear cell infiltrates. ANA (speckled pattern) and anti-RNP antibodies were positive. ABG was unremarkable. PFT showed a restrictive pattern (VC, 70.6%; DLCO, 77.2%). HLA serotypes were as follows: A24, A26, B15 (62, 76), B61, Cw10, DR9, DR53 and DQ9. CXR and CT revealed early-stage IP (Fig. 1D and E). VATS biopsy specimens of left lower lobe segments revealed mild and homogeneous changes typical of nonspecific IP (NSIP) (Fig. 1F). She was administered methylprednisolone pulse therapy (1 g/day for 3 days) followed by oral prednisolone (50 mg/day), which suppressed active myositis and IP. Immunohistochemical analysis was performed on lunginfiltrating cells utilizing biopsy specimens. Substantial infiltrations of mononuclear cells were noted in both patients. Most mononuclear cells were CD3 T cells, accompanied by a subtle infiltration of B cells (CD20), and a minimal number of monocytes (CD19). Of infiltrating T cells, more CD4 than CD8 cells were noted in both cases. Letters to the Editor

Effects of CD80 and CD86 on cytokine production in patients with wasp-venom allergy who receive venom immunotherapy.

Several studies have provided evidence that activation of antigen-specific T cells requires interactions between CD28 on T cells and its ligands, CD80 and CD86, on antigen-presenting cells (APCs). However, the effects of CD80 and CD86 on cytokine production in patients with Hymenoptera venom allergy who receive venom immunotherapy remain unclear. We examined the effects of CD80 and CD86 on Th1- and Th2-cytokine production before and after venom immunotherapy in patients with wasp-venom allergy. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with wasp-venom allergy before and after three months of venom immunotherapy. CD4+ T cells and monocytes were isolated as APCs from PBMCs and were cocultured with wasp venom in the presence of anti-CD80 or -CD86 blocking antibodies. Interleukin (IL)-4, IL-10, and interferon (IFN)-gamma were measured by enzyme-linked immunosorbent assay. The expression of CD80 and CD86 on CD14+ PBMCs was detected by fluorescence-activated cell-sorter analysis. The expression of CD86, but not that of CD80, on CD14+ PBMCs cocultured with venom increased after three months of venom immunotherapy, but not before venom immunotherapy. Blockade of CD86 reduced IL-10 production after three months of venom immunotherapy. IL-10 production promoted by CD86 costimulation may be involved in the mechanism of venom immunotherapy in patients with venom allergy.